Tableting process



United States Patent 3,395,211 TABLETIN G PROCESS Kurt Hans Wielich,Cranbury, and Henry B. Zimmerman, Westfield, N.J., assignors toCarter-Wallace, Inc., New York, N.Y., a corporation of Maryland N0Drawing. Filed Dec. 10, 1965, Ser. No. 513,094 4 Claims. (Cl. 424-46)ABSTRACT OF THE DISCLOSURE A two-cycle tableting process for producingcompressed tablets containing a low-melting or adhesive active medicinalmaterial which comprises introducing into the tablet die a firstgranulation containing an abrasive material, compressing :and ejectingthe resulting tablet, introducing into the same die a second granulationcontaining the lowmelting or adhesive material, compressing and ejectingthe resulting tablet. The cycle can be repeated until the desired numberof tablets is obtained.

The present invention relates to a tableting process. More particularly,the invention rel-ates to a novel tableting process which makes itpossible to produce acceptable tablets from materials or combinationswhich, under standard operating conditions, would normally tend toadhere to the dies and punches of a tableting machine.

The problem of compressing low melting or adhesive pharmaceuticalmaterials into tablets which are pharmaceutically acceptable and whereinthe active material is physiologically available to the user has facedthe pharmaceutical industry for years. It said low melting materials arecompressed into tablets under high compression forces, the activeingredient tends to melt due to the heat generated on compression.'Resolidification of the material after said melting usually results intablets which have slow disintegration or dissolution rates and which,consequently, do not release the active material into the patientssystem at a satisfactory rate. In addition, the melt ing caused by thehigh compression forces results in high percentages of fractured orlaminated tablets, which are commercially unusable.

If, on the other hand, lower compression forces are used, some of thetableting granulation tends to adhere to the dies and punch faces of thetableting machine. Consequently, the resulting tablets are physicallydeformed.

Various methods of producing acceptable tablets containing low meltingor adhesive materials have been proposed in the past. One of suchmethods comprises greatly increasing the amount of excipient customarilyused in the tablet granulation. While, in some cases, it is possible toproduce acceptable tablets by this method, such tablets are generallymuch larger than standard pharmaceutical tablets and due to their size,are unsatisfactory from a marketing standpoint.

It is an object of the invention to provide a method for producingacceptable tablets which contain one or more low-melting and/or adhesivematerials. It is another object of the invention to provide a method ofproducing acceptable pharmaceutical tablets containing one or morelow-melting and/or adhesive active materials whereby the resultingtablets have satisfactory disintegration or dissolution rates. It is afurther object of the invention to produce acceptable pharmaceuticaltablets containing tybamate. These and other objects of the inventionwill become apparent to those skilled in the art in the light of theinstant specification.

In its broad aspect, the invention relates to a method of producingacceptable compressed tablets from a tablet granulation containing alow-melting or adhesive material, said method comprising the steps of:

3,395,211 Patented July 30, 1968 ice (a) Introducing into a tablet die afirst tablet granulation containing an abrasive material;

(b) Compressing said first granulation into an abrasive tablet under ahigh compression force;

(c) Ejecting said abrasive tablet from said tablet die;

(d) Introducing into said tablet die a second tablet granulationcontaining a low-melting or adhesive material;

(e) Compressing said second granulation into a production tablet under alow compression force;

(f) Ejecting said production tablet from said tablet die; and

(g) Repeating steps (a) to (f) until the desired number of productiontablets are produced.

Among the low melting or adhesive materials which can be processed intoacceptable pharmaceutical tablets according to the method of the presentinvention, there can be mentioned, for example, tybamate (chemically,Z-methyl 2 propyltrimethylene butylcarbamate carbamate), mephenesin,guaianesin, theophylline, meprobamate-aluminum hydroxide combinations,and the like.

As 'used herein and in the appended claims, the terms low and high, asapplied to the compression forces used during the tableting of,respectively, the production tablets and the abrasive tablets, signifycompression forces which are lower or higher than those commonly usedduring standard tableting operations.

For example, it has been found that suitable tablets can be preparedfrom low melting or adhesive materials by employing a compression force,as measured at the punch face, in the range of from about 2 to about 8tons per square inch and preferably about 4 tons per square inch. Saidforces, which are unusually low by pharmaceutical tableting standards,would normally yield tablets which would adhere to the dies and punchfaces of the tableting machine and which consequently, would bephysically deformed. However, when such low compression forces areutilized in the process of the invention, there are produced eleganttablets which have suitable disintegration and dissolution rates.

The high compression forces used in the preparation of the abrasivetablets are in the range of from about 15 to about 25 tons per squareinch and higher. The upper limit is generally determined by the physicalcapabilities of the tableting machine employed in the process since ithas been found that, the higher the compression force, the better thecleaning effect will be on the punch and die walls.

In a preferred aspect of the invention, it has been found that optimumresults can be obtained by varying the degree of penetration of thepunch into the die cavity during the compression of the productiontablets and the abrasive tablest. In compressing the production tabletsa penetration of about /a inch or less is preferred whereas incompressing the abrasive tablets a penetration of inch or more ispreferred. The deeper penetration used in compressing the abrasivetablets increases the amount of travel of the tablet along the die walland, consequently, gives maximum die wall cleaning.

The abrasive materials which are used in the present process arematerials which are sufficiently abrasive as to effectively clean thedie walls and punch faces without damaging same. In addition, for thesake of avoiding contamination, it is preferred that said materials benon-toxic. Furthermore, for efficiency and economy, preferred materialsshould be easily compressible into coherent tablets, preferably withoutthe need of complicated granulation stages.

Suitable abrasive materials useful in the practice of the inventioninclude, for example, lactose, wood cellulose, magnesium hydroxide,tricalcium phosphate, dicalcium phosphate, and mixtures thereof.

The following are typical compositions which can be used in the practiceof the present invention to produce abrasive tablets which willeffectively clean the dies and punches. Compositions I-IV can betableted directly after the components thereof are intimately admixedwhereas composition V should be subjected to a stagewise granulationprior to tableting in a manner known in the art. The percentages inparenthesis indicate the most preferred compositions.

Composition I Components: Weight percent Anhydrous lactose (75) 65-90Wood cellulose (24.5) 10-35 Magnesium stearate (0.5) 0.5-1.0

Composition II Components: Weight percent Anhydrous lactose (75) 65-90Magnesium hydroxide (24.5) 10-35 Magnesium stearate (0.5) 0.5-1.0

Composition III Components: Weight percent Anhydrous lactose (75 65-90Wood cellulose (12.5) 5-18 Magnesium hydroxide (12.0) 5-18 Magnesiumstearate (0.5) 0.5-1.0

Composition IV The low melting or adhesive materials are prepared fortableting in accordance with the present invention in manners well knownto those skilled in the art by combining the active material withconventional excipients. A suitable granulation to be compressed intoacceptable tablets according to the present teachings would contain atleast 50 percent by weight of the low melting or adhesive material, fromabout to about 30 percent by weight of a suitable filler, from about 5to about percent by weight of a disintegrating agent, from about 2 toabout 15 percent by weight of a binding agent, and from about 1 to about5 percent by weight of a lubricant.

In general, all conventional excipients are operable in the practice ofthe invention. It has been found, however, that wood cellulose is thepreferred filler.

For example, a preferred granulation for compounding tybamate granulesinto tablets has the following composition:

The process of the invention is conveniently carried out in a standarddouble rotary tablet press, with a plurality of dies arranged tocompress and eject two tablets per die per revolution of the head. Twofeed hoppers are provided, one filled with the abrasive composition andthe other with the production granulation.

The press is adjusted so that, during the first half revolution of thehead, each successive die is filled with the abrasive material which isthen compressed into a tablet at a pressure of from about 15 to tons persquare inch and at a punch penetration of about inch or more. Thetablets thus formed are then ejected and collected into a suitablecontainer.

The cycle is then repeated during the second half revolution of thehead, using the production granulation and compressing same into tabletsat a pressure of from about 2 to about 8 tons per square inch and with apunch penetration of about A: inch or less.

The abrasive tablets produced can, of course, be crushed by any suitablemeans and the resulting material reused in the practice of theinvention.

The following example is illustrative of the invention.

Tybamate tablets were produced according to the practice of theinvention. The tybamate granulation was prepared by coating 67.0 partsof tybamate powder with 3.5 parts of gelatin (applied as a 10%solution). After the resulting granules were dried, they were admixedwith 13 parts of Wood cellulose and again coated with 1.5 parts ofstarch (applied as a paste having a 5% starch concentration). The finalgranulation was obtained by admixing the dried double-coated granuleswith 3.0 parts of Wood cellulose, 10.5 parts of starch and 1.5 parts ofstearic acid.

The granulation was compressed into tablets using a standard doublerotary tablet press equipped with dies of inch diameter.

The abrasive material used had the following composition.

Components: Weight percent Anhydrous lactose (75 65-90 Wood cellulose(24.5) 10-35 Magnesium stearate (0.5) 0.5-l.0

Tablets were compressed from the tybamate granulation and from theabrasive material according to the present invention.

The punch penetration for the production tablets was maintained at inchwhile the compression force was varied as indicated below. In tabletingthe abrasive material, the punch penetration and the compression forcewere maintained at inch and 22 tons per square inch respectively.

The tybamate tablets thus produced were examined visually and samplesthereof were then tested for disintegration using the U.S.P. XVI methodfor disintegration.

The tablets exemplified by Sample No. 1 were found to be too soft forcommercial handling and use. The tablets exemplified by Samples Nos. 5-9were observed to be fractured or laminated and, therefore, commerciallyunacceptable. Tablets produced in accordance with the present invention,and exemplified by Samples Nos. 2-4, were well-formed commerciallyacceptable tablets.

The results are as follows:

Compression Force Disintegration (Tons per square inch) Time Sample No.:

1 0 5 see.

2. 1 10 sec. 4. 2 30 see. 6. 3 2 min. 14.0 10 min. 18.2 11 min. 22. 4 8min. 26. 6 8 min. 30. 8 8 min.

As will be apparent from the above table, the tablets produced inaccordance with the present invention also possess excellentdisintegration rates.

The invention in its broader aspect is not limited to the specificsteps, methods and compositions described, but departure may be madetherefrom within the scope of the accompanying claims without departingfrom the principles of the invention and without sacrificing its chiefadvantages.

For example, the present process will also permit the compression ofother soft materials used in the pharmaceutical industry, such assuppositories. A suitable granulation made of suppository medicamentsand excipients may be compressed according to the claimed method byusing suitable dies and punches to produce the conventional suppositoryshapes.

Suppository granulations to be compressed may contain, for example, abismuth salt as an astringent, benzocain as a local anesthetic, andmeprobamate as a tranquillizer. The medicaments may be granulated with aCarboWax-4000 to 6000 and suitable fillers as excipients.

Effervescent laxative suppository compositions containing CarboWax-6000,sodium bicarbonate and sodium biphosphate have been compressed accordingto the method of the present invention.

What is claimed is:

1. A method of producing compressed tablets from a tablet granulationcontaining a low-melting or adhesive active medicinal material, saidmethod comprising the steps of:

(a)introducing into a tablet die a first tablet granulation containingan abrasive material selected from the group consisting of lactose, woodcellulose, magnesium hyydroxide, tricalcium phosphate, dicalciumphosphate, and mixtures thereof;

(b) compressing said first granulation into an abrasive tablet by meansof a tablet punch at a compression force of from about 15 to about 25tons per square inch and with a punch penetration into the die cavity ofat least about inch;

(c) ejecting said abrasive tablet from said tablet die;

(d) introducing into said tablet die a second tablet granulationcontaining at least 50 percent by weight of a low melting or adhesiveactive medicinal material;

(e) compressing said second granulation into a production tablet bymeans of said tablet punch at a compression force in the range of fromabout 2 to about 8 tons per square inch and with a punch penetrationinto the die cavity of up to about /8 inch;

(f) ejecting said production tablet from said tablet die;

and

(g) repeating steps (a) to (f) until the desired number of productiontablets are produced.

2. A method of producing compressed tablets from a tablet granulationcontaining tybamate, said method comprising the steps of:

(a) introducing into a tablet die a first tablet granulation containingan abrasive material selected from the group consisting of lactose, woodcellulose, magnesium hydroxide, tricalcium phosphate, dicalciumphosphate, and mixtures thereof;

(b) compressing said first granulation into an abrasive tablet by meansof a tablet punch at a compression force of from about to about tons persquare inch and with a punch penetration into the die cavity of at leastabout inch;

(c) ejecting said abrasive tablet from said tablet die;

(d) introducing into said tablet die a second tablet granulationcontaining tybamate;

(e) compressing said second granulation into a tybamate tablet by meansof a tablet punch at a compression force in the range of from about 2 toabout 8 tons per square inch and with a punch penetration into the diecavity of up to about inch;

(f) ejecting said tybamate tablet from said tablet die;

and

(g) repeating steps (a) to (f) until the desired number of tybamatetablets are obtained.

3. The method of claim 2 wherein said second tablet granulation containsat least percent by weight of tybamate.

4. The method of claim 3 wherein the tybamate content is about 67percent by weight.

References Cited UNITED STATES PATENTS 3,042,531 7/1962 Leal et al l6782XR 3,096,248 7/1963 Rudzki l6782 3,116,204 12/1963 Siegel et a1. l6782XR 3,134,719 5/1964 Sheth et a1. l6782 3,175,948 3/1965 Kotf et a1.l6782 XR 3,293,132 12/1966 Stoyle et al. l6782 3,332,848 7/1967 Magidl6782 3,344,030 9/1967 Stevens et a1 16782 LEWIS GOTTS, PrimaryExaminer.

S. K. ROSE, Assistant Examiner.

